CN1273467C - Beta-lactam compounds, process for producing the same and serum cholesterol-lowering agents containing the same - Google Patents

Abstract

Novel beta-lactam compounds represented by the following general formula (I) or pharmaceutically acceptable salts thereof which are useful as serum cholesterol-lowering agents: (I) wherein A1, A3 and A4 represent each hydrogen, halogen, C1-5 alkyl, C1-5 alkoxy, -COOR1, a group represented by the following general formula (b): (b) wherein R1 represents hydrogen or C1-5 alkyl, or a group represented by the following general formula (a): (a) wherein R2 represents -CH2OH, -CH2OC(O)-R1 or -CO2-R1; R3 represents -OH or -OC(O)-R1; R4 represents -(CH2)kR5(CH2)l- wherein k and l are each 0 or an integer of 1 or above provided k+l is an integer of not more than 10; and R5 represents a single bond, -CH=CH-, -OCH2-, carbonyl or -CH(OH)-; provided that at least one of A1, A3 and A4 is a group represented by the above formula (a); A2 represents C1-5 alkyl, C1-5 alkoxy, C1-5 alkenyl, C1-5 hydroxyalkyl or C1-5 carbonylalkyl; and n, p, q and r are each an integer of 0, 1 or 2.

Description

β-lactam compounds, processes for preparing these compounds, and serum cholesterol-lowering agents containing these compounds

field of invention

The present invention relates to novel β-lactam compounds, processes for their preparation and serum cholesterol-lowering agents containing these compounds.

Background of the invention

Hypercholesterolemia is a risk factor for atherosclerotic heart disease. Atherosclerotic heart disease is a major cause of death and cardiovascular morbidity worldwide (Lipid Research Clinics Program. J. Am. Med. Assoc., 1984, 251, 351 or 365). Recently, HMG-CoA reductase inhibitors have been used clinically as cholesterol-lowering agents. HMG-CoA reductase inhibitors show strong plasma cholesterol-lowering activity, however, they have also been reported to have unsatisfactory side effects (Mevacor in Physician's DeskReference, No. 49 ED, Medical Economics Date Production Company, 1995, 1584). Therefore, effective and safe serum cholesterol-lowering drugs are desired.

It has been reported that naturally occurring glycosides have serum cholesterol-lowering activity (M.A.Farboodniay Jahromi et al., J.Nat.Prod., 1993, 56, 989., K.R.Price, TheChemistry and Biological Significance of Saponins in Foods and FeedingStuffs.CRC Critical Reviews in Food Science and Nutrition, CRC Press, 1987, 26, 27). These glycosides are believed to lower serum cholesterol levels by inhibiting the absorption of cholesterol in the small intestine (P.A. McCarthy et al., J. Med. Chem., 1996, 39, 1935). In addition, it has been reported that some β-lactam compounds have cholesterol-lowering activity (S.B.Rosenblum et al., J.Med.Chem., 1998, 41, 973B.Ram etc., Indian J.Chem., 1990, 29B, 1134.USP 489, 3597).

The β-lactam compound itself has weak cholesterol absorption inhibitory activity, and the glucuronide of the β-lactam compound has stronger cholesterol absorption inhibitory activity than the parent β-lactam compound. During the absorption process, the β-lactam compound after oral administration is rapidly glucuronidated in the small intestine, and the resulting glucuronide derivatives are secreted into the small intestine through the biliary tract. These derivatives combined with β-lactam-O-glucuronic acid are located in the mucosal layer of the small intestine, that is, the action and inhibition site of cholesterol absorption (M. van Heek et al., Brit. J. Pharmacol., 2000, 129, 1748. , J. Pharmacol. Exp. Ther., 1997, 283, 157). Since the above-mentioned β-lactam compounds exhibit serum cholesterol-lowering activity in the small intestine in the form of β-lactam-O-glucuronic acid-bound derivatives, synthesis of β-lactam compounds containing glucose or glucuronic acid Derivatives of these compounds have cholesterol-lowering activity (W.D. Vaccaro et al., Bioorg. Med. Chem. Lett., 1998, 8, 313). However, it is considered that the O-glycosidic bonds in these compounds are easily hydrolyzed by glycosidases present in the small intestine after oral administration, which means that the cholesterol-lowering activity of these compounds will be reduced in the small intestine. Considering that the active site of the β-lactam is the mucous layer of the small intestine, there is a need for better cholesterol absorption inhibitors that act efficiently and long-term only in the small intestine. It is desired that an ideal cholesterol absorption inhibitor is not absorbed in the small intestine and is eliminated without being absorbed in the small intestine so as to reduce side effects after absorption in the small intestine.

The main object of the present invention is to provide novel cholesterol-lowering drugs having β-lactam moieties and C-glycosides in the molecule, which are stable against glycosidase metabolism and acid or base hydrolysis. That is, the object of the present invention is to provide a hybrid molecule having a β-lactam and a C-glycoside as a cholesterol-lowering drug.

Detailed description of the invention

The present invention considers that the hybrid compound of β-lactam moiety and C-glycoside is stable to glycosidase metabolism and acid or base hydrolysis (R.J. Linhald et al., Tetrahedron, 54, 9913-9959, 1998). First, β-lactam-C-glycoside compounds are expected to be stable to glycosidases present in the small intestine, and these hybrids are likely to persist in the mucosal layer of the small intestine for a long time. Second, the present invention considers that these compounds are less absorbed in the mucous layer of the small intestine, thereby reducing side effects. In an effort to discover new beta-lactam compounds having serum cholesterol-lowering activity, the present inventors have found that compounds of general formula (I) are excellent cholesterol-lowering agents.

That is, the compound of the present invention has the following general formula (I) or a pharmaceutically acceptable salt thereof:

[wherein: A ₁ , A ₃ and A ₄ are a hydrogen atom, a halogen atom, an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, -COOR ₁ , the following formula (b) The group:

Or a group of the following formula (a):

Wherein: R ₂ is -CH ₂ OH, -CH ₂ OC(O)-R ₁ or -CO ₂ -R ₁ ; R ₃ is -OH or -OC(O)-R ₁ ; R ₁ is a hydrogen atom or has An alkyl group of 1-5 carbon atoms; R ₄ is (-CH ₂ ) _K R ₅ (CH ₂ ) ₁ -(k and 1 are 0 or 1 greater integer; k+1 is 10 or less than 10 integer); _R5 is a bond (single bond (-), -CH=CH-, _-OCH2- , carbonyl, or -CH(OH)-).

One of A ₁ , A ₃ and A ₄ in formula (I) must be the group mentioned in formula (a) above. _A2 is an alkyl chain having 1-5 carbon atoms, an alkoxy chain having 1-5 carbon atoms, an alkenyl chain having 2-5 carbon atoms, a hydroxyl group having 1-5 carbon atoms An alkyl chain or a carbonylalkyl chain having 2 to 5 carbon atoms. n, p, q or r is 0, 1 or 2].

In addition, the present invention relates to the preparation method of the compound of general formula (I) and its pharmaceutically acceptable salt, and this method comprises the compound of general formula (II):

Wherein: A ₁ , A ₂ , R ₃ and p are as defined above; X is selected from halogen atoms and optically active sultones,

Staudinger or Mannich reactions with compounds of general formula (III):

Wherein: A ₃ , A ₄ , R ₃ , n, q and r are as defined above.

The present invention also relates to another preparation method of compounds of general formula (I) and their pharmaceutically acceptable salts, which method comprises compounds of general formula (IV) in the presence of a base:

Wherein: n, q, r, A ₃ , A ₄ and R ₃ are as defined above,

With the reaction of general formula (V) compound:

Wherein: A ₁ , A ₂ , p, X and R ₃ are as defined above.

The present invention also relates to another preparation method of compounds of general formula (I) and their pharmaceutically acceptable salts, which method comprises the β-lactamization reaction of compounds of general formula (VI):

wherein: n, p, q, r, A ₁ , A ₂ , A ₃ , A ₄ and R ₃ are as defined above, and Y is an optically active sultone,

Compounds of general formula (I) and their pharmaceutically acceptable salts are produced.

The present invention also relates to serum cholesterol-lowering drugs containing compounds of general formula (I) and their pharmaceutically acceptable salts. In addition, the present invention relates to serum cholesterol-lowering agents for combined therapy with compounds of general formula (I) and beta-lactamase inhibitors.

The pharmaceutically acceptable salts of the present invention are described below. As an inorganic base salt, it refers to a sodium or potassium salt of the general formula (I). The organic acid salt refers to a salt of succinic acid, maleic acid, toluenesulfonic acid or tartaric acid. The compound of general formula (I) can be administered orally alone or mixed with a pharmaceutically acceptable carrier or diluent. They can be administered orally by standard pharmaceutical techniques in the form of powders, granules, tablets, capsules and also parenterally in the form of rectal administration, suppositories and injections.

The dose is 0.01-1000 mg per day, and is administered in single or multiple doses. However, it needs to be changed according to the patient's condition, age and weight. In addition, the combination of the compound of general formula (I) and a β-lactamase inhibitor can enhance the serum cholesterol-lowering activity.

β-lactamase inhibitors (such as clavulanic acid) are drugs that inhibit the degradation of the β-lactam ring caused by microorganisms.

The compounds are exemplified below, but not limited thereto.

1(4S ^* ,3R ^* )-4-{4-[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran -2-yl]phenyl}-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidin-2-one

2(4S ^* ,3R ^* )-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyridine Pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidin-2-one

3(3S, 2R, 4R, 5R, 6R)-2-[(4-{(4S ^* , 3R ^* )-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl Base) propyl]-2-oxoazetidin-4-yl}phenyl)methyl]-4,5-diacetyloxy-6-(acetoxymethyl)perhydrogenated-2H -pyran-3-yl acetate

4(4S ^* ,3R ^* )-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyridine Pyran-2-yl]methyl}phenyl)-1-(4-chlorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidin-2-one

5(4S ^* ,3R ^* )-4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyridine Pyran-2-yl]methyl}phenyl)-1-(4-methoxyphenyl)-3-[3-(4-fluorophenyl)propyl]azetidin-2-one

6(3S, 2R, 4R, 5R, 6R)-2-[(4-{(4S ^* , 3R ^* )-1-(4-methoxyphenyl)-3-[3-(4-fluoro Phenyl)propyl]-2-oxoazetidin-4-yl}phenyl)methyl]-4,5-diacetyloxy-6-(acetoxymethyl)perhydrogenated- 2H-pyran-3-yl acetate

7(4S ^* ,3R ^* )-4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyridine Pyran-2-yl]methyl}phenyl)-1-(4-methylphenyl)-3-[3-(4-fluorophenyl)propyl]azetidin-2-one

8(3S, 2R, 4R, 5R, 6R)-2-[(4-{(4S ^* , 3R ^* )-1-(4-methylphenyl)-3-[3-(4-fluorobenzene Base) propyl]-2-oxoazetidin-4-yl}phenyl)methyl]-4,5-diacetyloxy-6-(acetoxymethyl)perhydrogenated-2H -pyran-3-yl acetate

9(4S ^* , 3R ^* )-4-(4-{[(5S, 2R, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyridine Pyran-2-yl]methyl}phenyl)-1-phenyl-3-[3-(4-fluorophenyl)propyl]azetidin-2-one

10(3S, 2R, 4R, 5R, 6R)-2-[(4-{(4S ^* , 3R ^* )-1-phenyl-3-[3-(4-fluorophenyl)propyl]- 2-Oxoazetidin-4-yl}phenyl)methyl]-4,5-diacetyloxy-6-(acetyloxymethyl)perhydro-2H-pyran-3- Acetate

11(4S ^* , 3R ^* )-4-(4-{[(5S, 2R, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyridine Pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)-3-[3-(phenyl)propyl]azetidin-2-one

12(4S ^* , 3R ^* )-4-(4-{[(5S, 2R, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyridine Pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]azetidin-2-one

13(3S, 2R, 4R, 5R, 6R)-2-[(4-{(4S ^* , 3R ^* )-1-(4-fluorophenyl)-3-[2-(4-fluorobenzene Oxy)ethyl]-2-oxoazetidin-4-yl}phenyl)methyl]-4,5-diacetyloxy-6-(acetoxymethyl)perhydrogenated- 2H-pyran-3-yl acetate

14(4S ^* , 3R ^* )-4-(4-{[(4S, 5S, 2R, 3R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyridine Pyran-2-yl]methoxy}phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidin-2-one

15(4S ^* , 3R ^* )-4-(4-{[(4S, 5S, 2R, 3R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyridine Pyran-2-yl]methoxy}phenyl)-1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]azetidine-2- ketone

16(4S ^* , 3R ^* )-4-(4-{[(4S, 5S, 2R, 3R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyridine Pyran-2-yl]methoxy}phenyl)-1-phenylmethyl-3-[3-(4-fluorophenyl)propyl]azetidin-2-one

17(2S, 3S, 4R, 5R, 6R)-6-[4-{(4S ^* , 3R ^* )-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl )propyl]-2-oxoazetidin-4-yl}phenyl)methyl]-3,4,5-trihydroxy perhydro-2H-pyran-2-carboxylic acid

18 2-{4-[(4S ^* , 3R ^* )-4-{[(5S, 2R, 3R, 4R, 6R)-3,4,5-trihydroxyl-6-(hydroxymethyl) perhydrogenated- 2H-pyran-2-yl]methyl}phenyl-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidinyl]phenoxy}-2- ethyl methpropionate

19 2-{4-[(4S ^* , 3R ^* )-4-{[(5S, 2R, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl) perhydrogenation- 2H-pyran-2-yl]methyl}phenyl-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidinyl]phenoxy}-2- Methpropionic acid

20 2-{4-[(4S ^* , 3R ^* )-4-{[(5S, 2R, 3R, 4R, 6R)-3,4,5-trihydroxyl-6-(hydroxymethyl) perhydrogenated- 2H-pyran-2-yl]methyl}phenyl-3-[3-(4-methylphenyl)propyl]-2-oxoazetidinyl]phenoxy}-2- ethyl methpropionate

21 2-{4-[(4S ^* , 3R ^* )-4-{[(5S, 2R, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl) perhydrogenation- 2H-pyran-2-yl]methyl}phenyl-3-[3-(4-methylphenyl)propyl]-2-oxoazetidinyl]phenoxy}-2- Methpropionic acid

22(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)azetidine alkan-2-one

23(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-phenylazetidin-2-one

24(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-methylphenyl)azetidine alkan-2-one

25(4S, 3R)-4-(4-{[(5S, 2R, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran- 2-yl]methyl}phenyl)-1-(4-fluorophenyl)3-[3-(4-fluorophenyl)propyl]azetidin-2-one

26(4S, 3R)-4-(4-{[(2S, 5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran- 2-yl]methyl}phenyl)-1-(4-fluorophenyl)3-[3-(4-fluorophenyl)-3-oxopropyl]azetidine-2- ketone

27(4S, 3R)-4-(4-{[(2S, 5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran- 2-yl]methyl}phenyl)-1-phenyl-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one

28(4S, 3R)-4-(4-{[(2S, 5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran- 2-yl]methyl}phenyl)-1-(4-methylphenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidine-2 -ketone

29 4-[(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R ,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-2-oxoazetidinyl] benzoic acid

30 4-[(4S, 3R)-4-(4-{[(2S, 5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H- Pyran-2-yl]methyl}phenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-2-oxoazetidinyl]benzoic acid

31 4-[(4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydrogenated-2H- Pyran-2-yl]methyl}phenyl)-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidinyl]benzoic acid

32 3-[(2E)-30-(4-fluorophenyl)-2-propenyl](4S, 3R)-4-(4-{[(2S, 5S, 3R, 4R, 6R)-3 , 4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)azetidine- 2-keto

33(4S, 3R)-4-{4-{[(2S, 5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran- 2-yl]phenyl}-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidin-2-one

34(4S, 3R)-4-{4-{[(2S, 5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran- 2-yl]phenyl}-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one

35(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]phenyl}-1-(4-fluorophenyl)azetidine-2 -ketone

36(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]phenyl}-1-(4-methylphenyl)azetidine-2 -ketone

37(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[(2S, 5S, 3R, 4R, 6R)-3,4 , 5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-1-phenylazetidin-2-one

38(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)azetidine alkan-2-one

39(4S, 3R)-3-[(3S)-3-(4-{[(2S, 5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl) Hydrogenated-2H-pyran-2-yl]methyl}phenyl)-3-hydroxypropyl]-1-phenyl-4-(4-fluorophenyl)azetidin-2-one

40(4R ^* , 3R ^* )-4-(4-{[(5S, 2R, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyridine Pyran-2-yl]methyl}phenyl)-3-[3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)azetidin-2-one

41 3-((3S)-3-Hydroxy-3-phenylpropyl)(4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5- Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-phenylazetidin-2-one

42 4-[3-((3S)-3-(4-fluorophenyl)-3-hydroxypropyl)(4S, 3R)-4-(4-{[(2S, 5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-2-oxoazetidinyl]benzene ethyl formate

43 4-(4-{[(5S, 2R, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl }phenyl)(4S,3R)-1-(4-methylphenyl)-3-[3-(4-fluorophenoxy)ethyl]azetidin-2-one

44 3-(3-phenylpropyl)(4S, 3R)-4-(4-{[(5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl) Perhydro-2H-pyran-2-yl]methyl}phenyl)-1-phenylazetidin-2-one

45(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-1,2-ethylidene}phenyl)-1-(4-fluorobenzene base) azetidin-2-one

46(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]ethyl}phenyl)-1-(4-fluorophenyl)azetidine alkan-2-one

47(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-1-propen-3-yl}phenyl)-1-(4-fluorobenzene base) azetidin-2-one

48(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-propyl}phenyl)-1-(4-fluorophenyl)azacycle Butan-2-one

49 3-((3S)-{4-[(2S, 5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2- Base]phenyl}-3-hydroxypropyl)(4S,3R)-1,4-bis(4-fluorophenyl)azetidin-2-one

50(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-methoxyprop-3-yl}phenyl)-1-(4-fluoro Phenyl)azetidin-2-one

51(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-methoxy-2-propen-3-yl}phenyl)-1-(4 -Fluorophenyl)azetidin-2-one

52(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-1-buten-4-yl}phenyl)-1-(4-fluoro Phenyl)azetidin-2-one

53(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-butyl}phenyl)-1-(4-fluorophenyl)azacycle Butan-2-one

54(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-1-penten-5-yl}phenyl)-1-(4-fluoro Phenyl)azetidin-2-one

55(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-pentyl}phenyl)-1-(4-fluorophenyl)azacycle Butan-2-one

56(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-ethyl-2-yl}phenyl)-1-phenylazetidine -2-one

57(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-ethyl-2-yl}phenyl)-1-(4-methylphenyl ) Azetidin-2-one

58(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R) -3,4,5-trihydroxy-6-(carboxy)perhydro-2H-pyran-2-yl]-ethyl-2-yl}phenyl)-1-(phenyl)azetidine -2-one

Typical preparation methods for the compounds of the present invention are given below, but are not limited to these compounds. A compound exhibiting specific optical activity can either be prepared as an optically active compound, or be isolated into an optically active compound by a suitable method, and its specific optical activity can be determined.

Compounds of the following general formula (I) can be obtained.

method 1

(1) (a) In the case where R ₄ is -CH ₂ - in the compound of general formula (I), the compound is prepared according to the following reaction.

Compound (1-2) obtained by reacting tetrabenzylglucuronolactone (1-1) with Tebbe's reagent (T.V.Rajanbabu et al., J.Org.Chem. 1986, 51, 5458) was used as a starting material. Compound (1-2) is subjected to Suzuki coupling reaction with compound (1-3) (C.R.Johnsone et al., Synlett 1997, 1406), followed by desilylation to obtain compound (1-4).

(TBAF=tetra-n-butylammonium fluoride)

(b) The aldehyde compound (1-5) is obtained by oxidizing the hydroxyl group of the compound (1-4) to obtain the compound (1-5).

(c) The aldehyde compound (1-5) and the amine compound (1-6) are condensed in the presence of molecular sieves and p-toluenesulfonic acid to obtain the compound (1-7).

The imine compound (1-7) and the compound (1-8) are subjected to a Staudinger reaction by refluxing in the presence of a base to obtain a β-lactam compound. In this reaction, when tri-n-butylamine is used as a base, a trans β-lactam compound is obtained. When LDA (lithium diisopropylamide) is used as a base, a cis β-lactam compound is obtained.

In addition, asymmetric β-lactam compounds can also be obtained by adding chiral ligands to the reaction mixture (A.M. Hafez et al., Org. Lett. 2000, 2(25), 3963-3965). Thereafter, the debenzylated compound (1-9) is obtained by catalytic hydrogenation.

(d) Compound (1-10) is obtained by acetylating compound (1-9).

(2) In the case where R ₄ is -CH ₂ - in the compound of the general formula (I), the compound is produced by the following reaction.

Compound (1-11) is reacted with Grignard reagent (1-12) to obtain compound (1-13) (MFWong et al., J.Carbohydr Chem.1996, 15(6), 763; CD.Hurd et al., J.Am . Chem. Soc. 1945, 67, 1972; H. Togo et al., Synthesis 1998, 409). Alternatively, compounds (1-11) are reacted with Grignard reagents (1-12), followed by dehydroxylation by triethylsilyl hydride. Converting the resulting hydroxyl group to a leaving group such as tosyl or halide and reacting the resulting compound with a base gives the alkene compound. Compound (1-13) is then obtained by hydrogenating the olefinic compound. Compound (1-13) is converted into Grignard reagent with metal magnesium, and reacted with DMF (dimethylformamide) to obtain compound (1-14). Compound (1-15) was obtained by reacting Grignard reagent of compound (1-13) with dry ice (CO ₂ ).

Compound (1-14) and compound (1-15) obtained by the above method are synthetic intermediates of general formula (I) of method 1-(1)-(c) and (d).

Method 2

(1) In the case where R ₄ is a direct link in the compound of the general formula (I), the compound is prepared by the following reaction.

Tetrabenzylglucuronolactone (1-1) was reacted with compound (2-1), followed by reaction with Et ₃ SiH and BF ₃ .Et ₂ O, to give compound (2-2) (JMLancelin et al., Tetrahedron Lett. 1983, 24, 4833). Compound (2-2) is a synthetic intermediate of general formula (I) of method 1-(1)-(b), (c) and (d).

(2) In the case where R ₄ is a direct link in the compound of general formula (I), the compound is prepared by the following reaction.

Compound (2-4) is obtained by reacting compound (1-11) with Grignard reagent (2-3) (F. Marquez et al., An. Quim., Ser. C. 1983, 79(3), 428).

(where X is as above)

Compound (1-14) is obtained by converting the methyl group of compound (2-4) into an aldehyde compound (P.S. Portoghese et al., J.Med.Chem. 2000, 43, 2489).

Compound (2-2) is obtained by reducing compound (1-14) with NaBH ₄ .

Method 3

(1) In the case where R ₄ is -OCH ₂ - in the compound of the general formula (I), the compound is produced by the following reaction.

(a) prepared by known methods (D.Zhai et al., J.Am.Chem.Soc.1988, 110, 2501; P.Allevi et al., J.Carbohydr.Chem.1993, 12(2), 209) Compound (3-1) is subjected to Mitsunobu reaction with compound (3-2) to give compound (3-3).

(b) Compound (3-4) is obtained by reducing the methyl carboxyl group of compound (3-3) to alcohol group with LiAIH ₄ .

Compound (3-4) is a synthetic intermediate of general formula (I) of method 1-(1)-(b), (c) and (d).

Method 4

In the case where one of A ₁ , A ₃ and A ₄ is the following group in the compound of the general formula (I), the compound is prepared by the following reaction.

Compound (4-1) is reacted with alkyl 2-bromoisolactate (4-2) in the presence of K ₂ CO ₃ , followed by hydrogenation to obtain the compound of general formula (I). Alternatively, compound (4-3) is obtained by hydrolysis with lithium hydroxide, followed by deprotection to obtain compound of general formula (I).

Method 5

In case _R2 is _-CO2H in the compound of general formula (I), said compound is prepared by the following reaction.

Compound (5-1) is oxidized with TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, radical) to obtain compound (5-2).

Method 6

Compound (6-3) is obtained by reacting compound (6-1) with compound (6-2). Compound (6-3) is oxidized to a sulfone compound, followed by Ramberg-Böcklund reaction (P.S.Belica et al., Tetrahedron Lett.1998,39,8225; F.K.Griffin et al., Tetrahedron Lett.1998,39,8179), to obtain compound (6-4). Compound (6-4) is hydrogenated followed by reaction with TBAF to give compound (1-4). Compound (1-4) can be used as a synthetic raw material in order to obtain a compound of general formula (I) according to method 1.

Method 7

(1) In the case where R ₃ is -OH- and -OC(O)R ₁ in the compound of the general formula (I), the compound is produced by the following reaction.

By glycosidating compound (7-1) with compound (1-11) in the presence of Lewis acid (BF ₃ .Et ₂ O, SnCl ₄ , AgOTf-Cp ₂ HfCl ₂ , etc.), compound (7- 3) (RR Schmidt et al., Synthesis 1993, 325). In a two-step reaction process, the first step is O-glycosidation and the second step is the rearrangement of O-glycosides to C-glycosides. Furthermore, the compound (7-3) can be converted into the compound (7-4) by esterifying the hydroxyl group of the phenol. Compound (7-3) and compound (7-4) can be used as synthetic raw materials in order to obtain compounds of general formula (I) according to methods 1 and 3.

(2) In the case where R ₃ is -OH- and -OC(O)R ₁ in the compound of the general formula (I), the compound is prepared by the following reaction.

Compound (7-6) obtained by the same method as method 7-(1) is deprotected to obtain compound (7-7). Triflatation of one of the hydroxyl groups of the compound followed by reaction with carbon monoxide affords compound (7-3) (R.E. Dolle et al., Chem. Commun. 1987, 904). Compound (7-3) is used as the starting material of the general formula (I) in Processes 7-(1), 1 and 3.

Compound (7-3) can also be obtained by carrying out the same coupling reaction between compound (7-11) and compound (1-11) to obtain compound (7-12), followed by Haloform reaction of acetyl group to obtain compound (7-3) (S. Kajigaeshi et al., Synthesis 1985, 674).

(3) In the case where R ₃ is -OH- and -OC(O)R ₁ in the compound of the general formula (I), the compound is prepared by the following reaction.

Compound (7-10) is obtained by C-glycosidation of the aryl group of compound (7-9) according to method 7(1). Compound (7-10) is used as the starting material of method 8 general formula (I).

(where Z is as above)

Method 8

Production method of optically active compound (I).

(a) Using E. Wunsch's method, the hydroxyl group of D-p-hydroxyphenylglycine (8-1) is benzylated to obtain compound (8-2) (Chem. Ber. 1958, 91, 543).

Compound (8-3) is obtained by protecting the amino group of compound (8-2) with a Boc group.

Compound (8-3) was converted into compound (8-4) by homologation (W.W. Ogilvie et al., Bioorg. Med. Chem. 1999, 7, 1521). Then, the Boc group of compound (8-4) is deprotected to obtain compound (8-5).

Using W.W.Ogilvie's method (W.W.Obilvie, Bioorg.Med.Chem. 1999, 7, 1521), compound (8-5) was cyclized to give β-lactam (8-6).

Compound (8-5), which is an optically active compound, can also be obtained by the following method.

That is, compound (8-9) is obtained by reacting compound (8-7) with an optically active amino acid derivative (8-8) in the presence of an acidic catalyst. Compound (8-9) is directly reduced to compound (8-11). It can also be reduced by alkenes (e.g. NaHB(OAc) ₃ , NaBH ₄ ) and treated with strong acids (e.g. HCO ₂ H, Et ₃ SiH) (C. Cimarell et al., J. Org. Chem. 1996, 61.5557) or hydrogenolysis, Compound (8-11) was obtained. Compound (8-11) is transesterified with BnOH to obtain compound (8-5). According to the same method as above, compound (8-5) is converted into compound (8-6).

By D.M.T.Chan's method (Tetrahedron Lett. 1998, 39, 2933), the β-lactam compound (8-6) is N-alkylated, followed by debenzylation to obtain the compound (8-12).

Compound (8-13) is obtained by Suzuki coupling reaction of compound (8-12) and glucose derivative (1-2) according to the method of C.R. Johnson (C.R. Johnson et al., synlett 1997, 1406).

Reaction of compounds (8-13) with LDA followed by C-alkylation with methyl acrylate affords compounds (8-14).

The ester group of compound (8-14) is converted into an acid chloride, and coupled with compound (8-15) using the Negishi method to obtain compound (8-16).

Compound (8-16) is debenzylated to generate compound (8-17), followed by E.J.Corey method (E.J.Corey et al., J.Am.Chem.Soc.1987,109,7925), compound (8-17 ) asymmetric reduction of the ketone group.

(b) Compound (8-13) is reacted with LDA followed by reaction with compound (8-20) to give compound (8-21). Compound (8-22) is obtained by hydrogenating compound (8-21).

In the general formula (I) in the case of A ₁ is the following compounds

For example, according to Method 8, compound 39 is prepared from the following compound (8-23) corresponding to compound (8-15).

In the general formula (I) in the case of A ₄ is the following compounds

For example, according to Method 8, compound 38 is prepared from the following compound (8-24) corresponding to compound (8-12).

Compounds (8-25) can also be obtained by enzymatic separation of racemic compounds (S.J. Faulconbridge et al., Tetrahedron Lett., 2000, 41, 2679). Compound (8-25) can be converted into general formula (2) via Suzuki coupling mentioned above.

Method 9

Production method of optically active compound (II).

Through the K.Tomioka method (K.Tomioka et al., J.Chem.Soc., Chem.Commun.1999, 715), the compound (9-1) is condensed with the compound (9-2) to obtain the compound (9-3) . The compound of general formula (I) can be obtained by deprotecting compound (9-3). Compound (9-3) can also be obtained by reacting silyl enol ester with Lewis acid (instead of compound (9-1)).

Method 10

Production method of optically active compound (III).

Compound (10-1) is condensed with compound (9-2) by the method of E.J. Corey (E.J. Corey et al., Tetrahedron Lett. 1991, 32, 5287) to obtain compound (10-4). Compound (10-4) is deprotected to obtain the compound of general formula (I).

Method 11

Production method of optically active compound (IV).

Compound (11-3) is obtained by reacting (R)-(+)-2,10-camphorsultam (11-1) with acid chloride (11-2). Compound (11-5) is obtained by coupling reaction of compound (11-3) and compound (11-4) in the presence of Lewis acid (TiCl ₄ , BF ₃ .OEt ₂ ). Compound (11-5) is reacted with BSA followed by TBAF (tetra-n-butylammonium fluoride) to give β-lactam compound (11-6).

The obtained compound (11-6) was converted into compound (8-15) by the same method as method 8.

According to method 8, compound (11-6) can be used as a starting material of the compound of general formula (I). On the other hand, when compound (11-7) is used instead of compound (11-4), compound (11-8) corresponding to compound (11-6) can be obtained by the same method.

Compound (11-9) can be obtained from compound (11-8) by the same method as Method 7.

According to method 8, compound (11-9) can be used as a starting material of general formula (I).

Method 12

Compound (11-6) is subjected to a Heck reaction with compound (12-1) prepared by a reported method (M. Yokoyama et al., Synthesis 1998, 409) to give compound (12-2). (R.F. Heck et al., J. Am. Chem. Soc. 1968, 90, 5518). According to method 8, compound (12-2) can be used as a starting material of general formula (I).

Compound (12-2) is hydrogenated to give compound (12-3). According to method 8, compound (12-3) can be used as a starting material of general formula (I).

Method 13

In the presence of Lewis acid (BF ₃ .OEt ₂ , ZnCl ₂ , AgOTf), compound (13-1) C-glycoside was converted to compound (1-11) (R ₆ is -Me, -Br or -CH ₂ OTBS) Compound (13-2) was obtained (KC Nicolaou et al., J. Chem. Soc., Chem. Comm. 1984, 1153). R ₆ of compound (13-2) is converted into an aldehyde by the same method as method 1-(1)-(6), 1-(2) or 2-(2). According to method 1, the obtained compound can be used as a starting material of the general formula (I).

Method 14

Compound (14-1) is subjected to coupling reaction, such as Suzuki coupling reaction, and subjected to Grignard reaction (Angew. Chem. Int. Ed. Engl. 2000, 4415) or alkylation in the presence of a base. After deprotection, compound (14-3) is obtained.

Method 15

Compound (15-1) prepared by the method of L. Dheilly (L. Dheilly et al., Carbohydr. Res. 1992, 224, 301) is converted into compound (15-2) by reduction and halogenation. Compound (15-2) is converted into an organometallic reagent (Grignard reagent, organic reagent), followed by a coupling reaction with compound (15-3) in the presence of a palladium or nickel catalyst. Compound (15-4) is then obtained by cyclization.

Method 16

Compound (16-1) can be obtained by performing Heck reaction using compound (12-1) and compound (15-3) by the same method as method 12. According to method 17, compound (16-1) is transformed into general formula (I).

Method 17

Compound (17-1) is removed from camphorsultam by treatment with lithium hydroxide to give compound (17-2) (the camphorsultam can be collected and reused). Then, compound (17-2) is cyclized with POCl ₃ in a solvent such as dichloromethane or dichloroethane to obtain general formula (I). By using a condensing agent such as DCC (1,3-dicyclohexylcarbodiimide) or DEPC (diethylphosphorylcyanide) in the presence of a base in dichloromethane or DMF, the general Compounds of formula (I). Alternatively, use Mitsunobu reagent with Bu ₃ P or Ph ₃ P, DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate) or react with (Py S) ₂ , can also obtain the compound of general formula (I), or in the presence of NaH, after reacting with 2,6-dichloro-benzoyl chloride or 2,4,6-trichlorobenzoyl chloride, use a base such as NaOH The compound of general formula (I) can be obtained by solution treatment.

Or compound (17-2) is esterified to compound (17-3), and then in a solvent such as THF, with a base such as LDA, LiHMDS (bis(trimethylsilyl) lithium amide), NaHMDS (bis(trimethylsilyl) Methylsilyl) sodium amide), NaH, t-BuOK reaction, obtain general formula (I). The general formula (I) can also be obtained by reacting Grignard reagents such as EtMgBr and t-BuMgBr with compound (17-3). Using the same reaction as compound (17-1), the compound of general formula (I) is obtained.

Method 18

Compound (18-2) is obtained by _SeO2 oxidation of compound (18-4) or Pd(OAc) ₂ -benzoquinone- _HClO4 oxidation of compound (18-4), and then the ketone of compound (18-2) Asymmetric reduction of the group gives compound (18-3). Compound (18-3) can also be obtained by hydrogenating compound (18-4). The hydrogenation reaction proceeds stereoselectively when a chiral borane reducing agent is used.

In the general formula described in method 1 to method 18, A ₁ , A ₂ , A ₄ , R ₃ , R ₄ , p, q, r and Z are as described above, and R ₆ is -CH=CH ₂ , -CH ₂ OH. K is an integer ≥ 1, 1 is 0 or an integer ≥ 1, and k+1 is an integer ≤ 10.

Method 19

(R ⁷ is -OAc group or -OBn group)

Compound (19-2) is obtained by asymmetric reduction of compound (19-1). For asymmetric reduction, transition metal catalysts are used (R. Noyori et al., J. Am. Chem. Soc. 1987, 109, 5856). After converting the hydroxyl group of compound (19-2) into a leaving group, the obtained compound is cyclized to obtain compound (19-3). Alternatively, compound (19-3) can be directly obtained by Mitsunobu reaction of compound (19-2). Compound (19-3) is subjected to a Heck reaction with compound (12-1), followed by hydrogenation of the resulting double bond to give compound (19-4). Or make compound (19-3) and compound (19-5) carry out Negishi coupling reaction (T.Hayashi etc., J.Am.Chem.Soc.1984,106,158-163; A.Saiga etc., Tetrahedron Lett.2000 , 41, 4629-4632; C.Dai et al., J.Am.Chem.Soc., 2001, 123, 2719-2724), to obtain compound (19-4). Compound (19-4) can be used as a synthetic substance of general formula (I) according to Example 8.

Method 20

Synthesis of compound (19-3)

According to Example 19, compound (20-2) was obtained by subjecting imine compound (20-1) to asymmetric reduction. The ester group of compound (20-2) is hydrolyzed to the corresponding carboxylic acid compound, and the resulting carboxylic acid is subjected to β-lactamization using a condensation reagent such as DCC to obtain compound (19-3). Compound (19-3) can also be obtained by subjecting compound (20-2) to β-lactamation using, for example, EtMgBr. Compound (19-3) can be used as a synthetic substance according to the general formula (I) in Example 19.

Method 21

Synthesis of compound (21-10)

Compound (19-1) is reacted with a base, followed by addition of compound (21-1), to obtain compound (21-2). Compound (21-2) is converted to compound (21-4) by asymmetric reduction, or compound (21-2) is converted to compound (21-5) by reaction with compound (21-3).

Compound (21-4) is reacted with compound (21-3) to obtain compound (21-6). Thereafter, compound (21-6) is coupled with sugar compound (12-1 or 19-5) to obtain compound (21-8), and then β-lactam compound (21-10).

On the other hand, after compound (21-7) is obtained by asymmetric reduction of compound (21-5), the obtained compound (21-7) is coupled with sugar compound (12-1 or 19-5) to obtain compound (21-9). Compound (21-10) can also be obtained by β-lactamization of compound (21-9). Compound (21-10) can be used as a synthetic substance of general formula (I).

[Used as a cholesterol-lowering drug in hypercholesterolemic hamsters]

The hamsters were divided into groups of three and fed with a 0.5%-cholesterol diet (CLEA Japan Co., Ltd.) containing CE-2 for 4 days or 7 days. During the experiment, the normal diet group was fed standard CE-2. Each compound or vehicle (0.2 mL corn oil) was administered orally per 100 grams of body weight for 4 or 7 days from initiation of a high cholesterol diet. Twenty hours after the last dose, blood samples were collected from the abdominal aorta of non-fasted animals under ether anesthesia. Serum cholesterol was measured by immunoassay using the cholesterol E-test wako (Wako Pure Chemical Industries). The activity of the test compound is expressed as the percentage reduction of the test compound based on the elevated total cholesterol compared to the group treated with the non-treatment-high cholesterol diet alone. Among compounds 1-58, the test compounds with optical rotation values were evaluated as chiral compounds. The results are shown in the table below. Each value in the table shows the percent change, with negative values indicating positive cholesterol-lowering activity.

[Table 13] No. Test compound (mg/kg) Days of administration Serum cholesterol (%) 2 3 7 -120 13 20 4 -28 15 20 4 -twenty one twenty three 3 7 -177 twenty four 3 7 -156 28 3 7 -130 33 3 4 -67 38 10 4 -2 45 3 4 -136 46 3 4 -147 49 10 4 -55 56 0.3 4 -84.0 57 0.3 4 -81.3

[Biostability test]

For the evaluation of the stability of C-glycoside, according to Mark von Itzstein method (Org.Lett., 1999,1,443-446), contrast C-allyl derivative (A) and O-allyl derivative ( B) Biostability against α-N-acetyl-D-galactosaminidase as a glycosidase.

[chemical formula 69]

Enzyme: α-N-acetylgalactosaminidase

0.32 units (1.69 units/mL in 0.1% BSA with 0.5M sodium citrate buffer)

Solvent: citric acid buffer (pD=3) 0.6mL

Temperature: 35°C

Method: Substrate (2 mg) was dissolved in citrate buffer (0.6 mL), and α-N-acetyl-galactosaminidase (0.32 units) was added. NMR spectra were measured at each constant time and the amount of remaining substrate was determined.

In Table 14 the results for the remaining substrates are given.

[Table 14]

From the above results, 78% of the O-allyl derivative (B) was significantly hydrolyzed after 24 hours. The C-allyl derivative (A), which displaces the ester bond to a C-C bond, was not affected by the enzyme as expected and no degradation was observed after 24 hours.

[Example]

The following examples are provided only to illustrate the preparation of the compounds and not to limit the invention.

Reference 1

4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-perhydro-2H-pyran-2-yl]methyl }phenyl)(4S ^* ,3S ^* )-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidin-2-one

Reference 1-a

Synthesis of compound (1-4)

50 mL of 9-BBN (0.5 M tetrahydrofuran solution) was added to a solution of compound (1-2) (5.37 g) in tetrahydrofuran (70 mL), and the mixture was refluxed for 5 hours, cooled to room temperature, and at room temperature for 15 minutes , 3M potassium phosphate (10 mL) was added to the mixture. To the resulting mixture was added 4-(tert-butyldimethyl-silyloxymethyl)bromobenzene (3.01 g) and _PdCl (dppf) (0.73 g) in N,N-dimethyl Formamide (100mL) solution. The mixture was stirred for 18 hours. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (15 mL). The mixture was stirred for 3 hours and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 3.58 g (2 steps, 56%) of compound (1-4).

Mass Spectrum (ESI) m/z: 662 (M+H ₂ O) ⁺

IR (KBr): 3430cm ^-1

¹ H-NMR (CDCl ₃ ): 2.71 (d, J=8.8, 13.2Hz), 3.13 (d, J=2.4, 14.2Hz), 3.32-3.36 (m, 2H), 3.45-3.50 (m, 1H) , 3.60-3.74(m, 4H), 4.48-4.68(m, 6H), 4.80-4.95(m, 4H), 7.18-7.37(m, 24H)

Reference 1-b

Synthesis of compound (1-5)

To a solution of compound (1-4) (3.6 g) in chloroform (22.0 mL) was added manganese dioxide (9.65 g), and the mixture was refluxed for 2 hours and cooled to room temperature. The mixture was filtered through a pad of celite and evaporated to yield 3.46 g (97%) of compound (1-5) as colorless crystals.

Mass Spectrum (ESI) m/z: 660(M+H ₂ O) ⁺

IR(KBr): 1692cm ^-1

¹ H-NMR (CDCl ₃ ): 2.77 (d, J=8.8, 14.2Hz), 3.16-3.20 (m, 1H), 3.32-3.36 (m, 2H), 3.49 (dt, J=2.0, 9.3Hz) , 3.61-3.66(m, 3H), 3.72(t, J=8.8Hz), 4.46-4.67(m, 4H), 4.81-4.97(m, 4H), 7.18-7.41(m, 22H), 7.74(d , J=8.3Hz), 9.95(s, 1H)

Example 1

(I) To a solution of compound (1-5) (3.46 g) in toluene (54.0 mL), molecular sieves (3.46 g), catalytic amounts of p-toluenesulfonic acid and p-fluoroaniline (0.61 mL) were added. The mixture was refluxed for 1.5 hours and filtered. The solvent was removed under reduced pressure, and the residue was carried on to the next reaction without purification.

(II) To a toluene (54.0 mL) solution of the compound obtained above, tributylamine (5.1 mL) and 5-(4-fluorophenyl)pentanoyl chloride (1.16 g) were added. After the mixture was refluxed for 15 hr, 1N hydrochloric acid (15 mL) was added to the mixture, and the mixture was stirred for 15 min. The organic layer was separated and washed with saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated. The residue was carried on to the next reaction without purification.

(III) A methanol-tetrahydrofuran (5/1) (6 mL) solution of the compound obtained above was hydrogenated in the presence of 10% palladium on carbon (200 mg) at room temperature for 5 hours. After removal of the catalyst, the reaction mixture was evaporated and the residue was chromatographed on silica gel (chloroform/methanol=10/1) to obtain 64 mg (26%) of compound 2.

Mass Spectrum (ESI) m/z: 554(M+H) ⁺

IR (KBr): 3376, 1737, 1503, ^1218cm-1

¹ H-NMR (CD ₃ OD): 1.82-1.98 (m, 4H), 2.65-2.78 (m, 3H), 3.09-3.39 (m, 7H), 3.64 (d, J=5.4, 12.2Hz), 3.77 -3.81(m, 1H), 4.94-4.98(m, 1H), 6.98-7.05(m, 4H), 7.18-7.22(m, 2H), 7.30-7.33(m, 4H), 7.38(d, J= 7.8Hz, 2H)

Example 2

Synthesis of Compound 3

4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-triacetoxy-6-(acetyloxymethyl)-perhydro-2H-pyran-2- Base]methyl}phenyl)-(4S ^* ,3S ^* )-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidine- 2-keto

To a solution of compound 2 (600 mg) in dichloromethane (11.0 mL) was added triethylamine (0.77 mL), acetic anhydride (0.49 mL) and a catalytic amount of 4-dimethylaminopyridine. The mixture was stirred at room temperature for 16 hours. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 600 mg (77%) of compound 3.

Mass Spectrum (ESI) m/z: 722 (M+H) ⁺

IR (KBr): 1749, 1506, 1380, 1221, 1029cm ^-1

¹ H-NMR (CDCl ₃ ): 1.82-1.84 (m, 4H), 1.93 (s, 3H), 1.97 (s, 1.5H), 1.98 (s, 1.5H), 1.99 (s, 1.5H), 2.00 (s, 1.5H), 2.02 (s, 3H), 2.61-2.64 (m, 2H), 2.79-2.82 (m, 2H), 3.07-3.08 (m, 1H), 3.56-3.69 (m, 2H), 4.02-4.23(m, 2H), 4.58(d, J=2.4Hz), 4.89-4.95(m, 1H), 5.03(t, J=9.3Hz), 5.17(t, J=9.3Hz), 6.90- 7.007(m, 4H), 7.08-7.12(m, 2H), 7.18-7.24(m, 6H)

Reference 2

Synthesis of compound (2-2)

4-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyl)benzyl alcohol

At -78°C, lithium anions were added dropwise to 7.31g of tetrabenzyl gluconolactone, and the latter was mixed with 6.66g of p-(tert-butyldiphenylsilyloxymethyl) at -78°C base) bromobenzene and 10 mL of n-butyllithium (1.57M in hexane). The mixture was stirred for 2 hours and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was carried on to the next reaction without purification. To a solution of the compound obtained above in dichloromethane (26 mL) were added triethylsilane (0.82 mL) and boron trifluoride-diethyl ether complex (0.33 mL) at -50°C. The mixture was stirred for 1.5 hours. Sodium bicarbonate solution was added. The mixture was stirred for 1 hour, then it was extracted with ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 1.48 g (15%) of compound (2-2).

IR(KBr): 3388, 1452, 1362, 1210, 1068, 1026cm ^-1

¹ H-NMR (CDCl ₃ ): 3.49-3.81 (m, 4H), 4.04-4.96 (m, 13H), 6.92-6.95 (m, 2H), 7.09-7.76 (m, 2H)

Reference 3-a

Methyl 4-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyl)methoxybenzoate

To a solution of compound (3-1) (555 mg), methyl p-hydroxybenzoate (153 mg) and triphenylphosphine (394 mg) in tetrahydrofuran (5.0 mL), diisopropyl azodicarboxylate (0.3 mL ). The mixture was stirred for 22 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to obtain 180 mg (26%) of compound (3-a).

IR (pure): 1713, 1605, 1434, 1359, 1248, 1164cm ^-1

¹ H-NMR (CDCl ₃ ): 3.49-3.77 (m, 7H), 3.89 (s, 3H), 4.07-4.11 (m, 1H), 4.19-4.22 (m, 1H), 4.51-4.60 (m, 4H) ), 4.82-4.89(m, 2H), 4.94(s, 2H), 6.87(d, J=8.8Hz, 2H), 7.15-7.36(m, 20H), 7.96(d, J=8.8Hz, 2H)

Reference 3-b

4-(2,3,4,6-Tetra-o-benzyl-β-D-glucopyranosyl)methoxybenzyl alcohol

At 0°C, 180 mg of compound 3-a in 5 mL of ether was added to a suspension of 10 mg of lithium aluminum hydride in 5 mL of ether. After the mixture was stirred at room temperature for 15 minutes, water (2.0 mL) and 15% sodium hydroxide solution (0.5 mL) were added, and the resulting suspension was filtered through a pad of celite. After removing the solvent, the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 160 mg (93%) of compound (3-b).

Mass Spectrum (ESI) m/z: 684 (M+H+Na) ⁺

IR (pure): 3442cm ^-1

¹ H-NMR (CDCl ₃ ): 1.56(s, 1H), 3.49-3.53(m, 1H), 3.60-3.77(m, 6H), 4.08-4.12(m, 1H), 4.20-4.23(m, 1H) ), 4.52-4.61(m, 6H), 4.85(Abq, J=11.2Hz, 2H), 4.93(s, 2H), 6.88(d, J=8.8Hz, 2H), 7.15-7.36(m, 22H)

Refer to 3-c

Synthesis of compound (1-14)

4-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyl)benzaldehyde

(1) To a solution of 4-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyl)toluene (0.3 g) in carbon tetrachloride (3 mL), add NBS (0.9mg) and Benzoyl Peroxide (0.05mg). The mixture was refluxed for 2 hours. After cooling to room temperature, diethyl ether (30 mL) was added to the mixture. The salt obtained was filtered off with suction. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/8).

(II) Sodium bicarbonate (45 mg) was added to a solution of the bromide (224 mg) obtained above in dimethyl sulfoxide (3 mL). After the mixture was stirred at room temperature for 1 hr and at 100°C for 4 hr, the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford compound (1-14) (26% for two steps).

Mass Spectrum (m/z): 436(M ⁺ ), 394, 307, 273, 245, 214, 163, 135, 105, 77, 51(BP)

IR (pure): 2914, 1641, 1437, 1257, 1017, 954, 708cm ^-1

¹ H-NMR (CDCl ₂ , 400MHz) δ: 1.96, 1.97, 2.06 (12H, each, s), 3.75-5.40 (7H, m), 7.96, 8.02 (4H, ABq), 10.06 (1H, s)

Example 3

2-(4-[4-{(5S,2R,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-perhydro-2H-pyran-2-yl} Methyl]phenyl)(4S ^* ,3S ^* )-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidine Alkyl)phenoxy-2-methylpropionic acid

(I) To a solution of compound (4-4) (3.19 g) in acetone (22.0 mL), ethyl 2-bromo-2-methylpropionate (0.77 mL) and potassium carbonate (0.97 g) were added. The mixture was refluxed for 40 hours, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3).

(II) A solution of compound 18 (2.93 g) obtained above in ethanol-tetrahydrofuran (1/1) (40 mL) was hydrogenated in the presence of 10% palladium on carbon (0.3 g) at room temperature for one hour. After removal of the catalyst, the filtrate was evaporated. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain 1.21 g (51.8% for two steps) of Compound 18.

To a solution of Compound 18 (400 mg) in tetrahydrofuran-water (5/1) (3 mL), lithium hydroxide (50 mg) was added. The mixture was stirred at room temperature for 8 hours, and the pH was adjusted to 3 by adding 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=5/1) to obtain 377 mg (51.0% for three steps) of Compound 19.

Mass Spectrum (ESI) m/z: 636(MH) ^-

IR(KBr): 3400, 1722, 1503cm ^-1

¹ H-NMR (CD ₃ OD): 1.53(s, 6H), 1.81-1.95(m, 4H), 2.65-2.68(m, 2H), 2.72-2.78(m, 1H), 3.09-3.41(m, 7H), 3.62-3.66(m, 1H), 3.77-3.82(m, 1H), 4.81(d, J=2.0Hz, 1H), 6.85(d, J=9.3Hz, 2H), 6.97-7.02(m , 2H), 7.18-7.22(m, 4H), 7.30(d, J=7.8Hz, 1H), 7.38(d, J=8.3Hz, 2H)

Example 4

Synthesis of Compound 17

6-[(4-{(2S ^* , 3S ^* )-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]-4-oxoazepine Butane-2-yl}(2S,3S,4R,5R,6R)-3,4,5-trihydroxyperhydro-2H-pyran-2-carboxylic acid

To a mixture of compound 2 (300 mg), 2,2,6,6-tetramethyl-1-piperidinyloxy radical (10 mg) and potassium bromide (10 mg) in acetonitrile (6.6 mL), was added Saturated sodium bicarbonate solution (6.6 mL) and sodium hypochlorite (6.6 mL). The mixture was stirred at room temperature for 3 hours, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain 90 mg (29.4%) of Compound 17.

Mass Spectrum (ESI) m/z: 566(MH) ^-

IR(KBr): 3388, 1737, 1509cm ^-1

¹ H-NMR (CD ₃ OD): 1.82-1.97 (m, 4H), 2.65-2.68 (m, 2H), 2.71-2.79 (m, 1H), 3.12-3.24 (m, 3H), 3.34-3.52 ( m, 3H), 3.62-3.68(m, 1H), 4.84(d, J=2.0Hz, 1H), 6.98-7.05(m, 4H), 7.18-7.21(m, 2H), 7.29-7.37(m, 6H)

Reference 4-a

Synthesis of compound (8-2)

D-p-Benzyloxyphenylglycine

To a solution of D-p-hydroxyphenylglycine (16.7 g) in 2N sodium hydroxide (50 mL) was added a solution of copper sulfate (12.5 g) in water (100 mL). The mixture was stirred at 60°C for 1 hour. After cooling to room temperature, 2N sodium hydroxide (50 mL), methanol (50 mL) and benzyl bromide (13.0 mL) were added. The mixture was stirred at room temperature for 20 hours. The resulting salt was collected by suction filtration, washed with water and acetone, the residue was dissolved in 1N hydrochloric acid (300 mL), and the mixture was stirred at room temperature for 1 hr. The resulting salt was collected by suction filtration, washed with water and acetone and dried to give 13.18 g (51.3%) of compound (8-2).

Mass spectrum m/z: 212 (M-45) ⁺ , 122, 91 (base), 65

IR(KBr): 3022, 1587, 1509, 1389, 1248, ^1008cm-1

¹ H-NMR (CD ₃ OD): 5.07 (s, 1H), 5.16 (s, 2H), 7.12 (d, J=6.8Hz, 2H), 7.34-7.48 (m, 5H), 7.45 (d, J =6.8Hz, 2H)

Refer to 4-b

Synthesis of compound (8-3)

D-p-benzyloxyphenyl-N-(tert-butoxycarbonyl)glycine

To a solution of compound (8-2) (12.53 g) in tetrahydrofuran-water (140 mL) were added triethylamine (16.4 mL) and di-tert-butyl-dicarbonate (13.5 mL) at 0°C. After stirring the mixture at room temperature for 4 hours, the mixture was concentrated under reduced pressure. A 10% citric acid solution was added to the residue to bring the pH to 4, and extracted with ethyl acetate (100 mL×3). The organic layer was washed with water (100 mL x 3), brine (100 mL), and dried (Na ₂ SO ₄ ). After removing the organic solvent under reduced pressure, 17.4 g (quantitative) of compound (8-3) was obtained.

Mass spectrum m/z: 357 (M ⁺ ), 331, 301, 283, 256, 212, 148, 120, 91 (base)

IR(KBr): 3298, 2968, 1791, 1656, 1608, 1506, 1452 ^{, 1392, 1242, 1161cm-1}

¹ H-NMR (CDCl ₃ ): 1.23 (s, 9H), 5.05 (bs, 3H), 6.94 (d, J=8.3Hz, 2H), 7.32-7.41 (m, 8H)

Refer to 4-c

Synthesis of compound (8-4)

(3S)-3-[4-(Benzyloxy)phenyl]-3-[(tert-butoxy)carbonylamino]propanoic acid benzyl ester

To a solution of compound (8-3) (14.4 g) in tetrahydrofuran (80 mL) were added triethylamine (5.9 mL) and isobutyl chloroformate (5.8 mL) at 0°C. After stirring the mixture for 40 minutes, an ethereal solution of diazomethane prepared from N,N-dimethylnitrosourea (30.0 g) and 40% potassium hydroxide solution (100 mL) was added. The mixture was stirred for 1.5 hours, then quenched with acetic acid. Diethyl ether (100 mL) and water (100 mL) were added to the mixture. The separated organic layer _was washed with saturated _Na2CO3 solution (100 mL x 2), brine (100 mL), _dried ( _Na2SO4 ) and evaporated. To a solution of the residue in tetrahydrofuran (80 mL)-water (15 mL) was added a solution of silver benzoate (0.93 g) in triethylamine (8.3 mL). After the mixture was stirred at room temperature for 2 hours, the mixture was diluted with diethyl ether (100 mL). The ether solution was washed with 10% hydrochloric acid (50 mL x 2), water (100 mL x 4), brine (50 mL), dried (Na ₂ SO ₄ ) and concentrated. To a solution of the residue in acetonitrile (80 mL), DBU (7.0 mL) and benzyl bromide (5.7 mL) were added. The mixture was stirred at room temperature for 4 hours and diluted with ethyl acetate. The ethyl acetate extract was washed successively with 10% acetic acid solution (50 mL x 2), saturated _Na2CO3 solution (100 _mL ), brine (100 mL), _dried ( _Na2SO4 ) and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 10.35 g (55.7%) of compound (8-4).

Mass spectrum m/z: 461 (M ⁺ ), 404, 360, 314, 270, 212, 180, 121, 91, 57 (base)

IR(KBr): 3394, 2956, 1731, 1689, 1500, 1290, 1224, 1149cm ^-1

¹ H-NMR (CDCl ₃ ): 1.51(s, 9H), 2.89-3.12(m, 2H), 5.10(s, 4H), 5.09-5.13(m, 1H), 6.99(d, J=8.8Hz, 2H), 7.30-7.54(m, 12H)

Reference 4-d

Synthesis of compound (8-5)

Benzyl (3S)-3-amino-[4-(benzyloxy)phenyl]propionate hydrochloride

To a solution of compound (8-4) (3.00 g) in ethyl acetate (30 mL) was added a solution of 17% hydrochloric acid in ethanol (10 mL). The mixture was stirred for 3 hours, and concentrated under reduced pressure. Ethyl acetate-hexane (1/4) was added to the residue for crystallization. The obtained crystals were filtered and dried to obtain 2.46 g (95.2%) of compound (8-5).

Mass Spectrum m/z: 361 (M-36.5) ⁺ , 344, 270, 147, 121, 91 (base), 65

IR(KBr): 3016, 2908, 1725, 1581, 1512, 1299, 1245, 1185cm ^-1

¹ H-NMR (CDCl ₃ ): 3.05 (d, J=6.4Hz, 18.3Hz, 1H), 3.27 (d, J=6.4Hz, 16.8Hz, 1H), 4.64-4.65 (m, 1H), 4.94- 5.03(m, 4H), 6.89(d, J=8.7Hz, 2H), 7.15-7.41(m, 12H), 8.77-8.78(m, 3H)

Reference 4-e

Synthesis of compound (8-6)

(4S)-4-[4-(Benzyloxy)phenyl]azetidin-2-one

To a suspension of compound (8-5) (6.48 g) in ethyl acetate, water (15 mL) and 1M potassium carbonate solution were added to make basic. The mixture was extracted with ethyl acetate (30 mL×2). The organic layer was washed with brine (50 mL), dried (Na ₂ SO ₄ ) and evaporated. To a solution of the residue in benzene (60 mL) were added triethylamine (3.6 mL) and chlorotrimethylsilane (2.7 mL). The mixture was stirred at room temperature for 14 hours and filtered through a pad of celite. The filtrate was evaporated under reduced pressure, the residue was dissolved in ether (65 mL), a 2M solution of tert-butylmagnesium chloride in ether (10.7 mL) was added at 0°C, and stirred at room temperature for 18 hours, then Saturated ammonium chloride solution (50 mL), ethyl acetate (50 mL) and 10% hydrochloric acid (50 mL) were added successively. After the resulting mixture was stirred at room temperature for 1 hour, the aqueous layer was washed with ethyl acetate. The combined ethyl acetate extracts were washed with water (50 mL), saturated NaHCO ₃ solution (50 mL), brine (50 mL), dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by silica gel column chromatography (chloroform/acetone=10/1) to obtain the target compound as a crude solid. The solid was purified with ethyl acetate-hexane to obtain 2.50 g (60.7%) of compound (8-6).

Mass spectrum m/z: 253 (M ⁺ ), 162, 91 (base), 65

IR(KBr): 3184, 1749, 1698, 1540, 1410, 1248, 1100cm ^-1

¹ H-NMR (CDCl ₃ ): 2.84-2.88 (d, J=1.0Hz, 2.4Hz, 15.1Hz, 1H), 3.39-3.44 (d, J=2.4Hz, 5.4Hz, 14.8Hz, 1H), 4.68 (d, J=4.9Hz, 14.9Hz, 1H), 5.08(s, 2H), 6.09(bs, 1H), 6.97(d, J=2.9Hz, 7.8Hz, 2H), 7.28-7.44(m, 7H )

Reference 4-f

Synthesis of (4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)azetidin-2-one

To a dichloromethane solution (10 ml) of compound (8-6) (1.00 g), triethylamine (0.8 mL), 4-fluorophenylboronic acid (1.11 g) and copper acetate (0.75 g) were added. The mixture was refluxed for 48 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined ethyl acetate extracts were washed successively with water (50 mL), 10% hydrochloric acid (50 mL), saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (benzene/diethyl ether=12/1) to obtain a solid, which was recrystallized from ethyl acetate-hexane to obtain 1.06 g (77.3%) of the target compound (8-26).

Mass spectrum m/z: 347 (M ⁺ ), 256, 210, 137, 91 (base), 65

IR(KBr): 1731, 1620, 1506, 1380, 1242cm ^-1

¹ H-NMR (CDCl ₃ ): 2.93 (d, J = 3.0Hz, 15.2Hz, 1H), 3.52 (d, J = 5.4Hz, 15.2Hz, 1H), 4.93 (d, J = 2.4Hz, 5.4Hz , 1H), 5.05(s, 2H), 6.90-6.99(m, 4H), 7.24-7.43(m, 9H)

Refer to 4-g

Synthesis of compound (8-27)

(4S)-1-(4-fluorophenyl)-4-(hydroxyphenyl)azetidin-2-one

A solution of compound 8-26 (2.00 g) obtained in the step of reference 4-f above in the presence of 5% palladium on carbon (0.20 g) in ethyl acetate-methanol (50 mL) was hydrogenated at room temperature for 9 hours. After removing the catalyst through a celite pad, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform/acetone=10/1) to obtain 1.36 g (91.9%) of compound (8-27).

Mass spectrum m/z: 257 (M ⁺ ), 214, 120 (base), 91, 58

IR(KBr): 3106, 1707, 1620, 1503, 1453, 1383, 1257, 1218cm ^-1

¹ H-NMR (CDCl ₃ ): 2.93 (d, J = 2.4Hz, 15.7Hz, 1H), 3.53 (d, J = 5.9Hz, 15.2Hz, 1H), 4.94 (d, J = 2.9Hz, 5.4Hz , 1H), 5.22(s, 1H), 6.85(d, J=8.3Hz, 2H), 6.93(s, J=8.8Hz, 2H), 7.23-7.27(m, 4H)

Reference 4-h

Synthesis of 4-[(2S)-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenyl trifluoromethanesulfonate

To a suspension of compound (8-27) (0.35 g) in dichloromethane (10 mL) were added pyridine (0.12 mL) and trifluoromethanesulfonic anhydride (0.26 mL) at 0°C. The mixture was stirred for 1 hour and poured into ice-cold water (20 mL). The resulting mixture was extracted with ethyl acetate (30 mL×2). The combined ethyl acetate extracts were washed with 10% hydrochloric acid (20 mL), saturated sodium bicarbonate solution (40 mL), brine (30 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to obtain 0.48 g (90.7%) of the target compound (8-28).

Mass spectrum m/z: 389 (M ⁺ ), 347, 252, 214, 186, 137, 119 (base), 69

IR(KBr): 1734, 1509, 1416, 1383, 1248, 1212, 1131, 900cm ^-1

¹ H-NMR (CDCl ₃ ): 2.94(d, J=2.5Hz, 15.2Hz, 1H), 3.16(d, J=5.9Hz, 15.2Hz, 1H), 5.04(d, J=2.5Hz, 5.4Hz , 1H), 6.98(t, J=8.8Hz, 2H), 7.21-7.25(m, 2H), 7.31(d, J=2.0Hz, 6.8Hz, 2H), 7.45(d, J=2.2Hz, 6.8 Hz, 2H)

Reference 4-i

Synthesis of compound (8-29)

(4S)-4-[4-{(2S, 5S, 3R, 4R, 6R)-6-[(benzyloxy)methyl]-3,4,5-tribenzyloxy}perhydro-2H- Pyran-2-yl]methyl)phenyl]-1-(4-fluorophenyl)azetidin-2-one

To a solution of compound (8-28) (0.32 g) in tetrahydrofuran (4.1 mL) was added 0.5M 9-BBN solution in tetrahydrofuran (3 mL), and the mixture was refluxed for 6 hr. After cooling to room temperature, 3M potassium phosphate solution (0.6 mL), tetrahydrofuran (4.7 mL), the compound obtained in reference 4-h (0.22 g) and PdCl ₂ (dppf) (0.042 g) were added to the mixture , and the resulting mixture was stirred at 50 °C for 16 hours. To the mixture were added water (30 mL) and ethyl acetate (30 mL), and the resulting mixture was filtered through a pad of celite. The filtrate was extracted with ethyl acetate (30 mL×2). The combined ethyl acetate extracts were washed with water (30 mL x 2) and brine (30 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain 0.209 g (45.4%) of compound (8-29).

Mass Spectrum (ESI) m/z: 800(M+Na(23)) ⁺ ,

IR(KBr): 2896, 1746, 1509, 1377, 1095, 1068, 750cm ^-1

¹ H-NMR (CDCl ₃ ): 2.69-2.75 (d, J=7.8Hz, 14.7Hz, 1H), 2.89 (d, J=2.5Hz, 15.1Hz, 1H), 3.12 (d, J=1.5Hz, 14.2Hz, 1H), 3.30-3.37(m, 2H), 3.46-3.53(m, 2H), 3.59-3.74(m, 8H), 4.45-4.64(m, 4H), 4.81-4.94(m, 5H) , 6.90(t, J=8.8Hz, 2H), 7.19-7.35(m, 26H)

Reference 4-j

Synthesis of compound (8-30)

3-{(4S, 3R)-4-[4-{(2S, 5S, 3R, 4R, 6R)-6-(benzyloxymethyl)-3,4,5-tribenzyloxy} perhydrogenation -2H-pyran-2-yl]methyl}phenyl]-1-(4-fluorophenyl)oxoazetidin-3-yl}

Methyl propionate

To a solution of 2M lithium diisopropylamide (1.3 mL) in tetrahydrofuran (3 mL) was added a solution of compound (8-29) (1.00 g) in tetrahydrofuran (1.5 mL) at -78°C, and the mixture was After stirring for 1 hour, a solution of methyl acrylate (0.132 g) in tetrahydrofuran (2 mL) was added to the mixture. The resulting mixture was stirred for 0.5 hr, the mixture was quenched with saturated ammonium chloride solution (30 mL), and extracted with ethyl acetate (60 mL×2). The combined ethyl acetate extracts were washed with water (50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain 0.793 g (71.8%) of compound (8-30).

Mass Spectrum (ESI) m/z: 864 (M+1) ⁺ ,

IR(KBr): 2854, 1740, 1509, 1452, 1362, 1215, 1140, ^1098cm-1

¹ H-NMR (CDCl ₃ ): 2.19-2.23 (m, 2H), 2.47-2.59 (m, 2H), 2.72 (d, J=8.8Hz, 14.6Hz, 1H), 3.04-3.13 (m, 2H) , 3.30-3.37(m, 2H), 3.42-3.48(m, 1H), 3.64(s, 3H), 3.61-3.74(m, 4H), 4.47-4.63(m, 5H), 4.81-4.94(m, 4H), 6.90(t, J=8.8Hz, 2H), 7.15-7.35(m, 26H)

Reference 4-k

Synthesis of compound (8-31)

(4S, 3R)-4-[4-({(2S, 5S, 3R, 4R, 6R)-6-(benzyloxy)methyl}-3,4,5-tribenzyloxy) perhydrogenation- 2H-pyran-2-yl]methyl)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azepine Cyclobutan-2-one

To a solution of compound (8-30) (1.75 g) in tetrahydrofuran-methanol (20 mL), water (5 mL) and lithium hydroxide (0.084 g) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was acidified by adding 10% hydrochloric acid, and extracted with ethyl acetate (30 mL×3). The combined ethyl acetate extracts were concentrated under reduced pressure, and the residue was passed through a short silica gel column (ethyl acetate/hexane=1/1) to obtain a crude product, which was used in the next reaction without further purification . To a dichloromethane (8.4 mL) solution of the compound obtained above was added a 2M dichloromethane solution of oxalyl chloride (0.84 mL), and the mixture was stirred at room temperature for 16 hr. Removal of the organic solvent afforded the crude acid chloride. To a suspension of zinc chloride (0.368g) in tetrahydrofuran (8mL), add 4-fluorophenylmagnesium bromide (made from magnesium (0.084g) and 4-bromofluorobenzene (0.47g) in tetrahydrofuran (8mL )preparation). The mixture was stirred at room temperature for 1 hour, then tetrakis(triphenylphosphine)palladium (0.068 g) was added at 10°C. After the mixture was stirred for 5 minutes, a solution of the acid chloride obtained above in tetrahydrofuran (7 mL) was added. The resulting mixture was stirred at room temperature for 1 hour, then quenched with 10% hydrochloric acid (20 mL). The mixture was extracted with ethyl acetate (50 mL×2). The organic layer was washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/5) to obtain 0.910 g (73.7%) of compound (8-31).

Mass Spectrum (ESI) m/z: 551(M+Na(23)+1) ⁺ ,

IR(KBr): 2920, 1746, 1690, 1610, 1310, 1280, 1240, 1100cm ^-1

¹ H-NMR (CDCl ₃ ): 2.23-2.42 (m, 2H), 2.72 (d, J=8.8Hz, 14.7Hz, 1H), 3.09-3.74 (m, 11H), 4.46-4.63 (m, 4H) , 4.66(d, J=2.5Hz, 1H), 4.81-4.94(m, 4H), 6.91(t, J=8.8Hz, 2H), 7.11(t, J=8.3Hz, 2H), 7.33-7.89( m, 26H), 7.96-8.00 (m, 2H)

Example 5

Synthesis of compound (26)

(4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxyphenyl)perhydro-2H-pyran-2 -yl]methyl}phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidine-2- ketone

To a solution of compound (8-31) (0.27 g) in dichloromethane (5.4 mL) was added a 1M solution of boron tribromide in dichloromethane (1.8 mL) at -78° C., and the mixture was stirred for 1 Hour. The mixture was poured into ice water (30 mL), extracted with chloroform (30 mL×3). The combined chloroform extracts were washed successively with water (50 mL), saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=8/1) to obtain 0.147 g (89.1%) of compound (26).

Mass Spectrum (ESI) m/z: 568(M+1) ⁺ ,

IR(KBr): 3400, 2902, 1737, 1680, 1596, 1506, 1386, 1224, 1152, 1134 ^{, 1086cm-1}

¹ H-NMR (CD ₃ OD): 2.28-2.34 (m, 2H), 2.74 (d, J=8.3Hz, 14.6Hz, 1H), 3.09-3.39 (m, 10H), 3.64 (d, J=5.3 Hz, 11.7Hz, 1H), 3.78(d, J=2.4Hz, 11.7Hz, 1H), 4.95(d, J=2.4Hz, 1H), 7.01-7.05(m, 2H), 7.22-7.26(m, 2H), 7.27-7.38(m, 6H), 8.06-8.10(m, 2H)

Example 6

Synthesis of compound (22)

3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-(4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)- 3,4,5-Trihydroxy(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)-azetidine-2 -ketone

To a solution of compound (8-32) (0.061 g) in dichloromethane (0.6 mL) was added a solution of compound (26) (0.115 g) in dichloromethane (2.8 mL) at -20°C, and the The mixture was stirred for 2 hours. The mixture was quenched by the addition of methanol (2 mL) and stirred for 1 hour. Ethyl acetate (30 mL) and 10% hydrochloric acid (30 mL) were added, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The organic layer was washed with water (30 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain 0.089 g (77.1%) of compound (22).

Mass Spectrum (ESI) m/z: 570(M+1) ⁺ ,

IR(KBr): 3370, 2902, 1725, 1506, 1389, 1218, 1083, 1011cm ^-1

¹ H-NMR (CD ₃ OD): 1.88-1.99 (m, 4H), 2.76 (d, J=8.3Hz, 14.2Hz, 1H), 3.09-3.40 (m, 7H), 3.64 (d, J=5.4 Hz, 11.5Hz, 1H), 3.79(d, J=2.0Hz, 11.7Hz, 1H), 4.65(d, J=4.8Hz, 6.4Hz 1H), 4.85(d, J=2.0Hz, 1H), 7.00 -7.09(m, 4H), 7.29-7.40(m, 8H)

Example 7

Synthesis of compound (8-33)

(4S, 3R)-4-[4-{(2S, 5S, 3R, 4R, 6R)-6-[(benzyloxy)methyl]-3,4,5-tribenzyloxy}perhydrogenated- 2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)-3-[(2E)-3-(4-fluorophenyl)-2-propenyl] Azetidin-2-one

To a solution of compound (8-29) in tetrahydrofuran (3 mL) was added 2M lithium diisopropylamide (0.6 mL) in tetrahydrofuran at -78°C, and the mixture was stirred for 30 minutes. 1.8 mL of DMPU (1,3-dimethyl-3,4-5,6-tetrahydro-2(1H)-pyrimidinone) was added to the mixture, and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of 4-fluorocinnamoyl bromide (0.111 g) in tetrahydrofuran (1.5 mL), and the resulting mixture was stirred for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (50 mL×2). The organic layer was successively washed with water (50 mL x 3), brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/5) to obtain 0.253 g (64.4%) of compound (8-33).

Mass Spectrum (ESI) m/z: 934(M+Na(23)) ⁺ ,

IR(KBr): 2890, 1746, 1509, 1383, 1359, 1224, 1137, 1098cm ^-1

¹ H-NMR (CDCl ₃ ): 2.63-2.88 (m, 3H), 3.12 (d, J=1.9Hz, 14.7Hz, 1H), 3.20-3.38 (m, 4H), 3.47-3.48 (m, 1H) , 3.59-3.74(m, 5H), 4.45-4.63(m, 4H), 4.65(d, J=2.4Hz, 1H), 4.81-4.94(m, 4H), 6.12(dt, J=6.8Hz, 14.6 Hz, 1H), 6.45(d, J=14.7Hz 1H), 6.90(t, J=8.8Hz, 2H), 6.95(t, J=8.7Hz, 2H), 7.14-7.35(m, 28H)

Example 8

Synthesis of compound (25)

4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl} Phenyl)-(4S,3R)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-propyl]azetidin-2-one

A solution of compound (8-33) (0.23 g) in methanol-tetrahydrofuran (10 mL) was hydrogenated in the presence of 5% palladium on carbon (0.115 g) at room temperature for 5 hours. After removing the catalyst through a pad of celite, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain 0.113 g (81.1%) of compound (25).

Mass Spectrum (ESI) m/z: 554 (M+1) ⁺ ,

IR(KBr): 3394, 2908, 1737, 1506, 1386, 1218, 1089cm ^-1

¹ H-NMR (CD ₃ OD): 1.88-1.95 (m, 4H), 2.66 (t, J=7.3Hz, 2H), 2.75 (d, J=8.3Hz, 14.2Hz, 1H), 3.09-3.40 ( m, 7H), 3.64(d, J=5.8Hz, 11.7Hz, 1H), 3.78(d, J=2.5Hz, 11.7Hz, 1H), 4.91(d, J=2.0Hz, 1H), 6.97-7.04 (m, 4H), 7.18-7.33 (m, 6H), 7.38 (d, J=8.3Hz, 2H)

Synthesis of compound (11-3)

5-(4-aza-10,10-dimethyl-3-dioxo-3-thiotricyclo[5,2,1,1,5]decane-4-yl)-5-oxo Methyl Valerate

At 0° C., to a solution of (R)-(+)-2,10-camphorsultam (0.89 g) in toluene (14 mL), sodium hydride (0.182 g) was added, and the mixture was stirred at room temperature for 20 minute. To the reaction mixture was added 5-chloro-5-oxo-pentanoic acid methyl ester (0.816 g), and the resulting mixture was stirred at room temperature for 1 hr. The reaction mixture was quenched by adding saturated ammonium chloride solution (40 mL), and extracted with ethyl acetate (50 mL×2). The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (chloroform/acetone=40/1, then ethyl acetate/hexane=1/2) to obtain 1.30 g (91.8%) of compound (11-3).

Mass spectrum m/z: 343 (M ⁺ ), 312, 279, 129 (base), 101

IR(KBr): 2944, 1720, 1689, 1440, 1413, 1389, 1335, 1215, 1050cm ^-1

¹ H-NMR (CD ₃ OD): 0.97(s, 3H), 1.16(s, 3H), 1.35-1.41(m, 2H), 1.87-2.12(m, 7H), 2.39(t, J=8.3Hz , 2H), 2.78(t, J=7.4Hz, 2H), 3.46(q, J=4.4Hz, 2H), 3.67(m, 3H), 3.85-3.88(m, 1H)

Reference 5-b

Synthesis of compound (11-10)

(4R)-4-{(1S)-(4-bromophenyl[(4-fluorophenyl)amino]methyl)-5-(4-aza-10,10-dimethyl-3 -Dioxo-3-thiotricyclo[5,2,1,1,5]decane-4-yl)-5-oxopentanoic acid methyl ester

To a solution of titanium tetrachloride (0.23 mL) in dichloromethane (10 mL) was added titanium tetraisopropoxide (0.2 mL) at 0°C, and the mixture was stirred for 5 minutes. A solution of compound (11-3) (0.65 g) in dichloromethane (3.5 mL) was added to the mixture, and stirred for 5 minutes. To the mixture was added diisopropylethylamine (0.72 mL), stirred for 1 hour, and then cooled to -20°C. At -20°C, (1Z)-1-aza-2-(4-bromophenyl)-1-(4-fluorophenyl)ethylene (1.15g) in dichloromethane (3.5mL) was added solution, and the resulting mixture was stirred for 3 hours. The reaction mixture was quenched by successive addition of acetic acid (1 mL) in dichloromethane (5 mL) and 10% hydrochloric acid (30 mL), extracted with ethyl acetate (50 mL×2). The organic layer was washed successively with water (50 mL), saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (chloroform/acetone=50/11, then ethyl acetate/hexane=1/2) to obtain 0.708 g (61.1%) of compound (11-10).

Mass spectrum m/z: 622(M+2) ⁺ , 620(M ⁺ ), 343, 278, 200, 135, 95

IR(KBr): 3376, 2944, 1734, 1683, 1509, 1437, 1269, 1131 ^{, 1059, 1008cm-1}

¹ H-NMR (CDCl ₃ ): 0.95(s, 3H), 0.95(s, 3H), 1.24-1.39(m, 2H), 1.60-2.04(m, 5H), 2.28-2.33(m, 2H), 3.45-3.57(m, 3H), 3.62(s, 3H), 3.79-3.91(m, 1H), 4.56(t, J=9.3Hz, 1H), 4.95(d, J=10.2Hz, 1H), 6.34 -6.38(m, 2H), 6.71-6.76(m, 2H), 7.17(d, J=8.3Hz, 2H), 7.41(d, J=8.3Hz, 2H)

Reference 5-c

Synthesis of compound (11-11)

Methyl 3-{(4S,3R)-4-(4-bromophenyl-1-(4-fluorophenyl)-2-oxoazetidin-3-yl}propanoate

At 50° C., to a solution of compound (11-10) (0.52 g) in toluene (10 mL), BSA (N, O-bistrimethylsilylacetamide, 0.41 g) was added, and the mixture was stirred for 30 minute. A 1M solution of tetrabutylammonium fluoride (0.84 mL) in tetrahydrofuran was added, and the resulting mixture was stirred at 50°C for 3 hr. After cooling to room temperature, the mixture was quenched with methanol (1 mL). The mixture was stirred for 5 minutes, then 10% hydrochloric acid (15 mL) was added. The reaction mixture was extracted with ethyl acetate (50 mL×2). The organic layer was washed successively with water (50 mL), saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to obtain 0.227 g (66.7%) of compound (11-11).

Mass Spectrum m/z: 407(M+2) ⁺ , 405(M ⁺ ), 270, 208, 169, 129(base), 95

IR(KBr): 2938, 1758, 1503, 1440, 1371, 1233, 1101cm ^-1

¹ H-NMR (CDCl ₃ ): 2.21-2.56 (m, 2H), 2.49-2.61 (m, 2H), 3.08-3.12 (m, 1H), 3.67 (s, 3H), 4.66 (d, J=2.5 Hz, 1H), 6.92-6.97(m, 2H), 7.18-7.22(m, 4H), 7.51(d, J=1.9Hz, 6.3Hz, 2H)

Reference 6

Synthesis of compound (12-4)

3-{(4S, 3R)-4-[4-(3-{(2S, 5S, 3R, 4R, 6R)-6-(benzyloxymethyl)-3,4,5-(tribenzyloxy base) perhydro-2H-pyran-2-yl}-1-propenyl)phenyl]-1-(4-fluorophenyl)oxoazetidin-3-yl}propionic acid methyl ester

To compound (11-11) (575mg) and 3-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyl)-1-propene (1.2g) triethyl To the solution of the amine (5 mL), tri-o-tolylphosphine (43 mg) and palladium acetate (16 mg) were added. The mixture was stirred at 100°C for 13 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (50 mL), the ethyl acetate layer was washed with 10% hydrochloric acid, brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain 1.1 g (87.0%) of compound (12-4).

This compound can be used as an intermediate for the compound of general formula (I) described in the synthesis references 4-i, 4-j and 4-k and examples 5, 6, 7 and 8.

Mass Spectrum (ESI) m/z: 890(M+1) ⁺

IR (pure): 3016, 2896, 1741, 1503, 1371, 1215, 1092, 831, 747cm ^-1

¹ H-NMR (CDCl ₃ ): 2.23 (q, J=7.8Hz, 2H), 2.44-2.60 (m, 4H), 3.11 (m, 1H), 3.33-3.44 (m, 3H), 3.58-3.75 ( m, 4H), 3.66(s, 3H), 4.54-4.94(m, 9H), 6.38(m, 2H), 6.91-7.32(m, 28H)

Reference 7

Synthesis of Compound 50

(4S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S, 5S, 3R, 4R, 6R)- 3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methoxyprop-3-yl}phenyl-1-(4-fluorophenyl) Azetidin-2-one

To a suspension of sodium hydride (4.5 mg) in DMF (N,N-dimethylformamide, 1 mL) at 0°C, was added 2,3,4,6-o-tetrabenzyl-1-deoxy- β-D-Glucopyranosylmethanol (62 mg) was dissolved in DMF (3 mL), and the mixture was stirred for 20 minutes. Add (4S,3R)-4-[4-(3-bromopropyl)phenyl]-3-[(3S)-(4-fluorophenyl)-3-hydroxypropyl]-2-nitrogen Heterobutan-2-one (57 mg) was dissolved in DMF (3 mL), and the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into ice-cold water (20 mL), extracted with ethyl acetate (30 mL×2). The organic layer was washed with water (30 mL x 2) and brine (40 mL), dried over anhydrous sodium sulfate and evaporated. A solution of the residue in tetrahydrofuran-methanol (1/1) (10 mL) was hydrogenated at room temperature in the presence of 5% palladium on carbon (50 mg) for 9 hr. After removal of the catalyst, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain 43 mg (61.2%) of Compound 50.

Mass Spectrum (ESI) m/z: 628(M+1) ⁺

IR (neat): 3388, 2902, 1734, 1509, 1389, 1218, 1080cm ^-1

¹ H-NMR (CD ₃ OD): 1.87-1.97 (m, 6H), 2.73 (t, J=7.4Hz, 2H), 3.10-3.5 (m, 1H), 3.12-3.39 (m, 5H), 3.52 -3.57(m, 2H), 3.53-3.69(m, 2H), 3.78(d, J=2.0Hz, 10.7Hz, 1H), 3.87(d, J=1.0Hz, 10.5Hz, 1H), 4.64(bt , 1H), 4.85(d, J=2.5Hz, 1H), 7.00-7.09(m, 4H), 7.27-7.37(m, 6H)

Example 9

Synthesis of compound 19-9

(4S)-4-(4-{[(2S,5S,3R,4R,6R)-6g(-benzyloxy)methyl-3,4,5-tribenzyloxy]perhydro-2H-pyridine Pyran-2-yl}ethyl-phenyl)-1-phenyl-azetidin-2-one

Reference 8-a

Synthesis of compound (19-6)

(3R)-3-(4-Bromophenyl)-3-hydroxy-N-phenylpropanamide

To a solution of 3-(4-bromophenyl)-3-oxo-N-phenylpropanamide (950 mg) in ethanol-dichloromethane (3:1, 4 mL), add RuCl ₂ [(S)- BINAP] (dichloro[(S)-(-)2,2'-bis(diphenylphosphine)-1,1'-binaphthyl]ruthenium(II)) catalyst (12 mg). The mixture was catalytically asymmetrically hydrogenated at 100 °C under a 5-atom _H2 atmosphere for 6 h. After cooling to room temperature, the mixture was concentrated. The obtained crystals were collected and dried to obtain 725 mg (yield 76%, asymmetric yield 99% ee) of compound (19-6).

m.p.＝210-212℃

[α] ^D : +33.0 (c=1.0, THF)

Mass spectrum m/z: 319 (M ⁺ ), 183, 157, 135, 93 (base), 65

IR(KBr): 3316, 1614, 1599, 1530, 1443, 1368 ^{, 1065, 693cm-1}

¹ H-NMR (DMSO): 2.69 (dd, J = 4.4Hz, 14.2Hz, 1H), 2.77 (dd, J = 8.8Hz, 14.2Hz, 1H), 5.16 (n, 1H), 5.69 (d, J =4.4Hz, 1H), 7.14(t, J=7.3Hz, 1H), 7.40(d, J=7.8Hz, 2H), 7.46(d, J=8.3Hz, 2H), 7.64(d, J=8.3 Hz, 2H), 7.69 (d, J=7.8Hz, 2H)

Reference 8-b

Synthesis of compound (19-7)

(4S)-4-(4-Bromophenyl)-1-phenyl-azetidin-2-one

To a solution of compound (19-6) (500 mg) in tetrahydrofuran (7 mL) were added DIAD (diisopropyl azodicarboxylate) (0.67 mL) and PPh ₃ (479 mg) at -78°C. The mixture was slowly warmed to room temperature and stirred for 4 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/5-1/2) to obtain 260 mg (55.2%) of compound 19-7.

m.p.＝113-115℃

[α] ^D : -146.0 (c=1.0, CHCl ₃ )

Mass Spectrum (ESI) m/z: 301 (M ⁺ ), 260, 184, 103, 77 (base)

IR(KBr): 1728, 1599, 1485, 1377, 1149, 828, 750cm ^-1

¹ H-NMR (CDCl ₃ ): 2.91 (dd, J=2.9Hz, 15.1Hz, 1H), 3.56 (dd, J=5.4Hz, 15.1Hz, 1H), 4.98 (dd, J=2.4Hz, 5.9Hz , 1H), 7.04-7.52(m, 9H)

Synthesis of compound (19-9)

To a solution of Zn(Cu) (106 mg) in tetrahydrofuran-HMPA (3:1, 4 mL) was added compound (19-8) (1.0 g), and the mixture was refluxed for 3 hr. Palladium acetate (1.7 mg) and 2-(di-tert-butylphosphino)biphenyl (4.4 mg) were added to the mixture at 0°C. After 5 minutes, compound (19-7) (223 mg) was added, and the mixture was warmed to room temperature. 10% Aqueous HCl (50 mL) and ethyl acetate (30 mL) were added to the mixture and filtered. The filtrate was extracted with ethyl acetate (50 mL×2). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain 480 mg (84.3%) of compound (19-9).

m.p.＝95-97℃

[α] ^D : -61.2 (c=1.0, CHCl ₃ )

ESI-MS (m/z): 796(M+Na) ⁺ , 774(M+1) ⁺

IR(KBr): 2854, 1749, 1599, 1497, 1452, 1371, 1212, 1068cm ^-1

¹ H-NMR (CDCl ₃ ): 1.71-1.75 (m, 1H), 2.04-2.10 (m, 1H), 2.63-2.74 (m, 1H), 2.81-2.87 (m, 1H), 2.94 (dd, J =2.4Hz, 15.1Hz, 1H), 3.18-3.22(m, 1H), 3.29(t, J=13.1Hz, 1H), 3.36-3.40(m, 1H), 3.53(dd, J=5.9Hz, 15.1 Hz, 1H), 3.59-3.75(m, 4H), 4.55-4.66(m, 4H), 4.80-4.88(m, 4H), 4.96-4.98(m, 1H), 7.02(t, J=6.8Hz, 1H), 7.14-7.37(m, 28H)

[Invention effect]

The present invention relates to novel β-lactam compounds, which are stable to β-glucosidase, acid and alkali metabolism and hydrolysis, and have a C-glycoside in the molecule, produce a strong serum cholesterol-lowering effect, and are used as a Serum Cholesterol Drugs.

Claims (7)

1. A compound of the following general formula (I) or a pharmaceutically acceptable salt thereof, Wherein: A ₁ , A ₃ and A ₄ are a hydrogen atom, a halogen atom, an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, -COOR ₁ , the following formula (b) Group: Or a group of the following formula (a):

Wherein: R ₂ is -CH ₂ OH group, -CH ₂ OC(O)-R ₁ group or -CO ₂ -R ₁ group; R ₃ is -OH group or -OC(O)-R ₁ Group; R ₁ is a hydrogen atom or an alkyl group with 1-5 carbon atoms; R ₄ is a -(CH ₂ ) _k R ₅ (CH ₂ ) ₁ -group, where 0≤k+1≤10; R ₅ is a single bond -, -CH=CH-, -OCH ₂ -, carbonyl or -CH(OH)-; and R ₄ is connected to the tetrahydropyran ring through a carbon-carbon bond, and in formula (I) One of A ₁ , A ₃ and A ₄ must be a group of the above formula (a); A ₂ is an alkyl chain having 1-5 carbon atoms, an alkoxy chain having 1-5 carbon atoms, Alkenyl chains having 2-5 carbon atoms, hydroxyalkyl chains having 1-5 carbon atoms or carbonylalkyl chains having 2-5 carbon atoms; n, p, q or r are 0, 1 or 2. 2. A method for preparing a compound of general formula (I) according to claim 1 and their pharmaceutically acceptable salts, the method comprising a compound of general formula (II):

Wherein: A ₁ , A ₂ , R ₃ and p are as defined in claim 1; X is selected from halogen atoms and optically active sultones, Staudinger or Mannich reactions with compounds of general formula (III): Wherein: A ₃ , A ₄ , R ₃ , n, q and r are as defined in claim 1. 3. A method for preparing a compound of the general formula (I) of claim 1 and their pharmaceutically acceptable salts, the method comprising the compound of the general formula (IV) in the presence of a base:

Wherein: n, q, r, A ₃ , A ₄ and R ₃ are as defined in claim 1, With the reaction of general formula (V) compound:

Wherein: A ₁ , A ₂ , p and R ₃ are as defined in claim 1, and X is as defined in claim 2. 4. A method for preparing the compound of general formula (I) of claim 1 and their pharmaceutically acceptable salts, the method comprising the β-lactamization reaction of the compound of general formula (VI):

Wherein: n, p, q, r, A ₁ , A ₂ , A ₃ , A ₄ and R ₃ are as defined in claim 1, and Y is an optically active sulphonamide, Compounds of general formula (I) and their pharmaceutically acceptable salts are produced. 5. A method for preparing compounds of general formula (VII) and their pharmaceutically acceptable salts,

Among them: A ₁ , A ₂ , A ₄ , R ₂ , R ₃ , n, p, q and r are as defined in claim 1; R ₇ is a single bond (-), -CH=CH-, -OCH ₂ - ; k is an integer of 0 or 1-9; The method involves compounds of general formula (VIII):

Wherein: A ₁ , A ₂ , A ₄ , R ₃ , n, p, q and r are as defined in claim 1; Z is selected from halogen atoms and triflate; k is an integer of 0 or 1-9 ; With the coupling reaction of general formula (IX) compound: Wherein: R ₂ and R ₃ are as defined in claim 1; R ₆ is a halogen atom, -CH=CH ₂ , -CH ₂ OH. 6. The serum cholesterol-lowering drug containing the compound of general formula (I) according to claim 1 and their pharmaceutically acceptable salts. 7. Serum cholesterol-lowering drug for combined therapy with the compound of general formula (I) according to claim 1 and a β-lactamase inhibitor.